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Rare Bleeding Disorders: Genetic, Laboratory, Clinical, and Molecular Aspects Maha Othman, MD, Phd1,2

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Rare Bleeding Disorders: Genetic, Laboratory, Clinical, and Molecular Aspects Maha Othman, MD, Phd1,2 Preface 575 Preface Rare Bleeding Disorders: Genetic, Laboratory, Clinical, and Molecular Aspects Maha Othman, MD, PhD1,2 1 Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada 2 St Lawrence College, Kingston, Ontario, Canada Semin Thromb Hemost 2013;39:575–578. Welcome to this special issue of Seminars in Thrombosis & sometimes be required to confirm diagnosis. Platelet defects Hemostasis. Characteristically, each issue of Seminars in can be caused by defective platelet receptors that affect the Thrombosis & Hemostasis is theme driven, with each new platelet binding to their ligands, impaired platelet structural issue devoted to a particular theme of relevance to thrombo- elements such as dense and α granules,3 or altered signal sis and hemostasis. The current issue of Seminars in transduction pathways. These disorders include Glanzmann Thrombosis & Hemostasis carries the theme of “Rare Bleeding thrombasthenia, Bernard–Soulier syndrome, platelet-type Disorders” (RBDs) and is an update on a previous issue von Willebrand disease (PT-VWD), Gray platelet syndrome, published in 2009 in this journal.1 In addition to a compre- and Scott syndrome.3,4 hensive update on the various rare coagulation factor defi- Whether of coagulation factor or platelet origin, the diag- ciencies or defects (fibrinogen, FII, FV, FV/FVIII, FXI, and FXIII), nosis and management of patients with RBDs can be difficult. the current issue also provides updates on a selected group of There is little information available about the clinical and rare platelet defects. However, some RBDs have not been laboratory features of some of these diseases and the clinical updated from the 2009 issue, as we believe there is insuffi- reports are usually based on single case reports or small case cient new significant information to warrant revision. series. In addition, there is a lack of consensus, or lack of The current issue Seminars in Thrombosis & Hemostasis awareness regarding expert consensus, with respect to the represents an attempt to enhance the awareness of various diagnostic process, which therefore often contributes to mis-/ RBDs among treating physicians, clinical and research labo- underdiagnosis. ratories, as well as research scientists interested in rare An introduction to this issue by Peyvandi et al provides an disorders. Each article details, for each RBD, the clinical overview of the worldwide efforts for classification, diagnosis, manifestations, the laboratory assays used in the diagnosis and management of RBDs.5 It updates general information (including problems with the laboratory evaluation), as well about RBDs published in the 2009 issue,2 discusses the data as the treatment options. Also, there is considerable discus- collection process worldwide, and also discusses the efforts sion on some controversial issues related to these diagnoses, made by the World Federation of Hemophilia (WFH; http:// and in some articles, on phenotype–genotypic relationships. www.wfh.org) and the International Rare Bleeding Disorders RBDs comprise bleeding disorders that have low preva- Database (RBDD; www.rbdd.org) in assessing the worldwide lence in the general population. The term often refers to prevalence of RBDs. This has more recently been added to by inherited deficiencies or defects in coagulation factors includ- the European Network of the Rare Bleeding Disorders and the ing fibrinogen (FI), prothrombin (FII), FV, FVII, combined FV/ Rare Bleeding Disorders Working Group under the umbrella FVIII defects, FX, FXI, and FXIII. These disorders constitute of the FVIII and FIX Scientific and Standardization Committee only approximately 3 to 5% of the coagulation disorders.2 The (SSC) of the International Society on Thrombosis and Haemo- clinical conditions associated with these deficiencies can be stasis. This article also discusses efforts to establish a consen- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. very diverse, ranging from mild to severe, and the diagnosis sus regarding the classification based on clinical severity, can be quiet challenging. Much less attention is given to RBDs issues related to the laboratory diagnosis and consensus (as that alter the function of circulating platelets, some of which related to the factor level in making the diagnosis), and also are not fully characterized and can also pose diagnostic the minimum coagulant activity required to prevent bleed- challenges. Impaired platelet-related hemostatic tests may ing. The article concludes that prospective large data collec- alert to these diagnoses; however, genetic analysis may tion in a multicenter multinational study is required to fill the Address for correspondence Issue Theme Rare Bleeding Copyright © 2013 by Thieme Medical DOI http://dx.doi.org/ Maha Othman, MD, PhD, Disorders: Genetic, Laboratory, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0033-1354560. Department of Biomedical and Clinical, and Molecular Aspects; New York, NY 10001, USA. ISSN 0094-6176. Molecular Sciences, Queen’s Guest Editor, Maha Othman, Tel: +1(212) 584-4662. University, Kingston, Ontario, K7L MD, PhD 3N6, Canada (e-mail: [email protected]). 576 Preface gaps in our knowledge of RBDs and to enable us to move genes being responsible for an intracellular trafficking (en- toward future clinical trials.5 doplasmic reticulum-to-Golgi transport) pathway required The second article by de Moerloose et al discusses various for the efficient secretion of FV and FVIII. These are the (lectin forms of fibrinogen defects.6 It details the clinical and labora- mannose-binding 1 (LMAN1) or multiple coagulation factor tory diagnosis of patients with afibrinogenemia, hypofibri- deficiency gene 2 (MCFD2) genes. The article focuses on the nogenemia, and dysfibrinogenemia. It also provides new molecular mechanism of F5F8D that facilitated an under- information regarding the genetics of this disease. Since the standing of the unique roles of LMAN1 and MCFD2 genes in first report of a genetic mutation in 1999, and even since the the secretion of FV/FVIII and highlighted the clinical benefits last issue on this topic in this journal few years ago,7large of the improved treatments of this bleeding disorder.12 numbers of mutations have been described. Despite the Combined FV and FVIII deficiency was also featured in the increase in the magnitude of genetic analysis in this field, earlier issue on RBDs.13 there is no clear relationship between the molecular defect The sixth article is by Duga and Ophira14 who provide a rich and the risk of thrombosis, and the explanation for the discussion of FXI deficiency—an injury-related bleeding disor- observed variability of clinical manifestations is still lacking der, common in Ashkenazi Jews but rare worldwide—and an and the genotype–phenotype correlations difficult to estab- update to a previous review on the same topic.15 There are more lish. Many challenges remain, particularly to achieve more than 220 mutations in the FXI gene reported in patients with FXI appropriate prevention and treatment of these diseases.6 deficiency, 7 of which show a founder effect. In addition to a The third article is by Lancellotti et al,8 and it provides an detailed review of the phenotypic and genotypic analysis and the update on the previous review on FII deficiency published in molecular basis of this bleeding disorder, the article discusses 2009 in Seminars in Thrombosis & Hemostasis.9 This update special issues in women and highlights the value of studies in focuses on the molecular diagnosis of FII deficiency caused by animal models with FXI deficiency. Treatment of patients with close to 40 different mutations and manifesting in two severe FXI deficiency remains challenging because factors influ- phenotypes, the true hypoprothrombinemia (type I; quanti- encing bleeding risks are still unknown and patients with severe tative deficiency) and (2) dysprothrombinemia (type II; qual- deficiency paradoxically develop thrombosis. Problems with itative deficiency), and sometimes in both when coexisting in laboratory diagnosis and the value of global hemostatic assays the compound heterozygous state. Prothrombin, the source of are highlighted. Treatment strategies and problems with treat- thrombin, is essential for the development of mammalian ment are also addressed.14 organisms and an undetectable plasma prothrombin is in- The final coagulation factor defect discussed in this issue is compatible with life. In addition to its procoagulant and by Schroeder and Kohler and on factor FXIII deficiency,16 and anticoagulant effects, thrombin affects the activity of multiple the article provides an update on the previously published cells that are engaged in several processes of the vascular and review on the same topic in the 2009 issue.17 The diagnosis of immune system such as platelets, endothelial cells, vascular this disease is challenging at both a clinical and laboratory smooth muscle cells, monocytes, T-lymphocytes, fibroblasts, level. The laboratory challenge compared with other RBDs is and mast cells. In addition to clinical, laboratory diagnosis, related to difficulties associated with timing of blood sampling, treatment via prothrombin products including recent devel- assay types, and interpretation of results. The article highlights opments in therapy, the genetics and structure and function the importance of newer specific FXIII assays and their prin- relationships were also discussed.8 ciples to avoid any missed diagnosis of FXIII
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